Drug delivery polymer and uses thereof

Patent metadata

Field	Value
Publication number	US-2016296631-A1
Application number	US-201615190018-A
Country	US
Kind code	A1
Filing date	Jun 22, 2016
Priority date	Apr 9, 2013
Publication date	Oct 13, 2016
Grant date	—

Abstract

Described herein are platinum-based brush-arm star polymers (Pt-BASPs), or a pharmaceutical composition thereof, for delivery of platinum-based agents, such as cisplatin. Also provided are methods and kits involving the Pt-BASPs, or a pharmaceutical composition thereof, for treating proliferative diseases such as cancers (e.g., lung cancer, head-and-neck cancer, esophagus cancer, stomach cancer, breast cancer, pancreas cancer, liver cancer, kidney cancer, or prostate cancer) in a subject.

First claim

What is claimed is:

1 . A platinum complex of Formula (I):

or a salt thereof,
wherein:
X 1 is F, C, Br, or;
X 2 is F, Cl, Br, or I;
each instance of R N1 and R N2 is independently hydrogen, optionally substituted C 1-6 alkyl, or a nitrogen protecting group; or two R N1 are taken with the intervening atoms to form a heterocyclic ring; or two R N2 are taken with the intervening atoms to form a heterocyclic ring; or R N1 and R N2 are taken with the intervening atoms to form a heterocyclic ring; and
n is 1, 2, 3, 4, 5, or 6.

2 . A platinum complex of claim 1 , wherein the complex is of Formula (II):

or a salt thereof.

3 . A platinum complex of claim 1 , wherein the complex is of Formula (II-a):

or a salt thereof.

4 . The platinum complex of any one of claims 1 - 3 , wherein n is 1.

5 . The platinum complex of any one of claims 1 - 3 , wherein n is 2.

6 . The platinum complex of any one of claims 1 - 3 , wherein n is 3.

7 . A method of preparing a platinum complex of claim 1 , the method comprising steps of:
(a) oxidizing a compound of Formula (s-1) with an oxidant

to give a compound of Formula (s-2):

wherein:
X 1 is F, Cl, Br, or I;
X 2 is F, Cl, Br, or I;
each instance of R N1 and R N2 is independently hydrogen, optionally substituted C 1-6 alkyl, or a nitrogen protecting group; or two R N1 are taken with the intervening atoms to form a heterocyclic ring; or two R N2 are taken with the intervening atoms to form a heterocyclic ring; or R N1 and R N2 are taken with the intervening atoms to form a heterocyclic ring; and
n is 1, 2, 3, 4, 5, or 6; and
(b) coupling the compound of Formula (s-2) with a compound of Formula (s-3):

to yield a platinum complex of Formula (I).

8 . The method of claim 7 , wherein the oxidant used in step (a) is H 2 O 2 .

9 . The method of claim 7 , wherein an activator is present in step (b).

10 . The method of claim 9 , wherein the activator is N,N′-Dicyclohexylcarbodiimide (DCC).

11 . A macromonomer of Formula (III):

or a salt thereof,
wherein:
a is an integer from 1 to 10, inclusive;
b is an integer from 1 to 5 inclusive;
c is an integer from 30 to 100 inclusive;
e is 0, 1, 2, 3, or 4;
L is —O—, —S—, —NR La —, —NR La C(═O)—, —C(═O)NR La —, —SC(═O)—, —C(═O)S—, —OC(═O)—, —C(═O)O—, —OC(═O)O—, —OC(═O)NR La —, —NR La C(═O)O—, trans-CR Lb ═CR Lb —, cis-CR Lb =CR Lb —, —C≡C—, —OC(R Lb ) 2 —, —C(R Lb ) 2 O—, —NR La C(R Lb ) 2 —, —C(R Lb ) 2 NR La —, —S(═O) 2 O—, —OS(═O) 2 —, —S(═O) 2 NR La —, —NR La S(═O) 2 —, or an optionally substituted C 1-10 hydrocarbon chain, optionally wherein one or more carbon units of the hydrocarbon chain is replaced with —O—, —S—, —NR La —, —NR La C(═O)—, —C(═O)NR La —, —SC(═O)—, —C(═O)S—, —OC(═O)—, —C(═O)O—, —OC(═O)O—, —OC(═O) NR La —, —NR La C(═O)O—, trans-CR Lb ═CR Lb —, cis-CR Lb ═CR Lb —, —C≡C—, —OC(R Lb ) 2 —, —C(R Lb ) 2 O—, —NR La C(R Lb ) 2 —, —C(R Lb ) 2 NR La —, —S(═O) 2 O—, —OS(═O) 2 —, —S(═O) 2 NR La —, or —NR La S(═O) 2 —, wherein each instance of R La is independently hydrogen, optionally substituted C 1-10 alkyl, or a nitrogen protecting group, and wherein each occurrence of R Lb is independently selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or two R Lb groups are joined to form an optionally substituted carbocyclic or optionally substituted heterocyclic ring, or R La and R Lb are joined to form an optionally substituted heterocyclic ring; and
M is hydrogen or a therapeutic, diagnostic, or prophylactic agent.

12 . The macromonomer of claim 11 , wherein L is of the formula:

wherein
p is an integer from 1 to 10, inclusive;
q is an integer from 1 to 10, inclusive;
each instance of R E is halogen, —CN, —NO 2 , —N 3 , optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted phenyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, —OR A , —N(R B ) 2 , —SR A , —C(═O)R A , —C(═O)OR A , —C(═O)SR A , —C(═O)N(R B ) 2 , —C(═O)N(R B )N(R B ) 2 , —OC(═O)R A , —OC(═O)N(R B ) 2 , —NR B C(═O)R A , —NR B C(═O)N(R B ) 2 , —NR B C(═O)N(R B )N(R B ) 2 , —NR B C(═O)OR A , —SC(═O)R A , —C(═NR B )R A , —C(═NNR B )R A , —C(═NOR A )R A , —C(═NR B )N(R B ) 2 , —NR B C(═NR B )R B , —C(═S)R A , —C(═S)N(R B ) 2 , —NR B C(═S)R A , —S(═O)R A , —OS(═O) 2 R A , —SO 2 R A , —NR B SO 2 R A , and —SO 2 N(R B ) 2 ;
each R A is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;
each R B is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or two R B groups are taken together with their intervening atoms to form an optionally substituted heterocyclic ring;
each k is independently 0, 1, 2, 3, 4, or 5;
g is an integer from 1 to 10, inclusive; and
h is an integer from 1 to 10, inclusive.

13 . The macromonomer of claim 11 , wherein the macromonomer is of Formula (III-a):

14 . The macromonomer of claim 11 , wherein the macromonomer is of Formula (III-b):

15 . The macromonomer of claim 11 , wherein the macromonomer is of Formula (III-c):

16 . The macromonomer of claim 11 , wherein the macromonomer is of Formula (III-d):

17 . The macromonomer of any one of claims 11 - 16 , wherein M is of the formula:

18 . The macromonomer of any one of claims 11 - 16 , wherein M is of the formula:

Assignees

• Massachusetts Inst Technology

Inventors

• Johnson Jeremiah A
• Liao Longyan

Classifications

• A61K47/60 Primary

  the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol · CPC title

• A61K31/555

  containing heavy metals, e.g. hemin, hematin, melarsoprol · CPC title

• A61K47/58

  obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. poly[meth]acrylate, polyacrylamide, polystyrene, polyvinylpyrrolidone, polyvinylalcohol or polystyrene sulfonic acid resin · CPC title

• A61K31/704

  attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin {(digitoxin A61K31/7048)} · CPC title

• C07F15/0093

  without a metal-carbon linkage · CPC title